ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5072C>T (p.Thr1691Ile) (rs80357034)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048762 SCV000076775 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1691 of the BRCA1 protein (p.Thr1691Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033), and in an individual affected with breast or ovarian cancer (PMID: 29470806). This variant has been observed to segregate with disease in a family affected with breast and pancreatic cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 37628). Experimental studies have shown that this missense change has a strong effect on BRCA1 transcriptional activity, growth complementation, peptide binding specificity, and protein folding (PMID: 20516115, 23867111). Also, an in vitro splicing analysis indicates that this variant induces out-of-frame skipping of exon 16 (also referred as exon 17) (PMID: 25724305). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000508659 SCV000568401 likely pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5072C>T at the cDNA level and p.Thr1691Ile (T1691I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). Using alternate nomenclature, this variant would be defined as BRCA1 5191C>T. Located in the third to last nucleotide of exon 16, this C>T substitution has been shown via a mini-gene assay to disrupt a natural splice donor site and cause abnormal splicing, leading to out-of-frame skipping of exon 16, published as exon 17 using alternate numbering (Ahlborn 2015). Additional in-vitro functional assays assessing the variant at the protein level, have demonstrated a severe folding defect as well as compromised phosphopeptide selectivity and transcriptional activation (Lee 2010). In addition, this variant has been shown to segregate with BRCA1-associated cancers by another clinical laboratory (ClinVar SCV000076775.4). BRCA1 c.5072C>T was not observed in large population cohorts (Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size, and other properties, this is considered a non-conservative amino acid substitution. The nucleotide which is altered, a cytosine (C) at base 5072, is conserved while the Threonine residue that is altered occurs at a position that is conserved in mammals and is located in the BRCT domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). Based on currently available evidence, we consider this variant to be likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508659 SCV000605900 likely pathogenic not provided 2019-08-05 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282608 chr). Predicted to have a damaging effect on the protein. Located in a potentially important domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Ambry Genetics RCV000509720 SCV000608092 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Sharing Clinical Reports Project (SCRP) RCV000031209 SCV000053809 uncertain significance Breast-ovarian cancer, familial 1 2007-03-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031209 SCV000145286 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Medical Genetics, National Institute of Health RCV000031209 SCV000787744 pathogenic Breast-ovarian cancer, familial 1 2018-05-14 no assertion criteria provided clinical testing We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This variant has previously been reported six times in families with hereditary breast and ovarian cancer syndrome. To date, there was a conflicting clinical significance of this variant in all databases from "Uncertain significance" in two reports to "likely pathogenic" in four others. This new report should contribute to improving the current pathogenicity ranking of this variant, c.5072C>T.

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